Clinical Ophthalmology
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Open Access Full Text Article
Prevalence of Signs and Symptoms of Dry Eye
Disease 5 to 15 After Refractive Surgery
Bjørn Gjerdrum 1,2
2 symptoms in patients with a history of laser vision correction (LVC) or implantable collamer
Kjell Gunnar Gundersen
Per Olof Lundmark 1
Rick Potvin 3
Bente Monica Aakre 1
1
Department of Optometry, Radiography
and Lighting Design, University of South-
Eastern Norway, Kongsberg, Norway;
2
Ifocus Eye Clinic, Haugesund, Norway;
3
Science in Vision, Akron, NY, USA
Correspondence: Bjørn Gjerdrum
Brønngata 36, Stavanger 4008, Norway
Tel +47 415 11 935
Email bjorn@ifocus.no
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http://doi.org/10.2147/OPTH.S236749
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ORIGINAL RESEARCH
This article was published in the following Dove Press journal:
Clinical Ophthalmology
Purpose: To compare the prevalence of dry eye disease (DED) as determined by signs and
lens (ICL) implantation 5–15 years ago with a matched control group with no history of
refractive surgery.
Patient and Methods: This was a cross-sectional case-control study. The subject popula-
tion included patients who had LVC or ICL 5 to 15 years ago. The control group was age
matched. A test eye was randomly chosen. Subjects were required to have good ocular
health. DED was evaluated using categorical cut-off criteria for tear film osmolarity (mea-
sured in both eyes), the subjective Ocular Surface Disease Index (OSDI), the dynamic
Objective Scatter Index (OSI), non-invasive keratography tear break-up time (NIKBUT),
meibography, and the Schirmer 1 test.
Results: The study included 257 subjects (94 LVC, 80 ICL, 83 control). The frequency of
hyperosmolarity was significantly higher in the LVC group vs the control (73% vs 50%, p =
0.002), In contrast, the frequency of subjective symptoms tended to be lower in the LVC
group than in the control group (19% vs 31%; p = 0.06). These differences were not seen
between the ICL and control group.
Conclusion: The results suggest that LVC may cause tear film instability as indicated by
hyperosmolar tears up to 15 years after surgery, with few subjective symptoms of dry eye.
This may have implications for IOL calculations for cataract or refractive lens exchange later
in life.
Keywords: tear film, hyperosmolarity, OSDI, post LVC
Introduction
Cataract surgery and RLE are common surgical procedures where the natural
crystalline lens of the eye is being replaced with an artificial intraocular lens
(IOL). Calculations of IOL power depend on measurements (biometry) of (at
a minimum) corneal curvature and axial length of the eye, but often include anterior
chamber depth and lens thickness as well. In general, the accuracy of the procedure
is high in patients without prior refractive surgery. However, for patients who have
previously undergone laser treatment for myopia the precision is much lower,
primarily due to 2 factors: inaccurate determination of the true total corneal
refractive power and incorrect estimation of the effective lens position.1,2
Traditional optical biometers use reflections from the pre-corneal tear film to
measure curvature as a part of the IOL power calculation. An uneven or unstable
tear film due to dry eye may directly reduce the accuracy and repeatability of these
measurements.3
Clinical Ophthalmology 2020:14 269–279 269
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Gjerdrum et al
Dry eye disease (DED) is a common disease and clin-
ical awareness has risen considerably around the world
through the last three decades.4 The TFOS DEWS II
(Tear Film and Ocular Surface Society International Dry
Eye Workshop II) report has defined dry eye as
. . . a multifactorial disease of the ocular surface character-
ized by a loss of homeostasis of the tear film, and accom-
panied by ocular symptoms, in which tear film instability
and hyperosmolarity, ocular surface inflammation and
damage, and neurosensory abnormalities play etiological
roles.5
While this definition is helpful, there is a lack of
standardized testing methods and criteria for categorizing
dry eye. As such, reported prevalence ranges from 5% to
50% when based on signs and symptoms, and up to 75%
based on signs only.5
Traditionally, classification has been based on considera-
tion of the source – evaporative or aqueous deficient. The
DEWS II revised classification indicates that these etiologies
are overlapping.4 In a sense, all forms of DED are evapora-
tive, because they are all associated with tear
hyperosmolarity.6 The new DED definition emphasizes the
role of homeostasis of the tear film, and diagnostic home-
ostasis marker tests are the minimum data set to be
collected.7 A recommended diagnostic test battery includes
screening with a questionnaire, and homeostasis markers
(non-invasive tear break-up time, osmolarity and staining).
DED is diagnosed if the patient has symptoms and one of the
homeostasis markers is positive, even without the full battery
of recommended tests.7 Further testing of tear volume and
lipids/meibomian glands is recommended for subtype classi-
fication before initiating appropriate treatment.7
Dry eye can be caused by different iatrogenic interven-
tions including systemic or local drugs, contact lenses, eye
surgery such as corneal refractive surgery and cataract
surgery.8 Laser in situ keratomileusis (LASIK) surgery is
among the most common operations performed world-
wide, with more than 16 million procedures globally to
2015 and more than three million procedures in the US
since 2015.9,10 Dry eye is the most commonly reported
problem following LASIK surgery.11,12 Corneal afferent
nerve fibers are severed during flap creation and stromal
ablation. The nerve damage interrupts the cornea to lacri-
mal gland reflex arc that impairs both basal and reflex tear
secretion, reduces blink rate, and causes a disruption of the
neurotrophic factors released from the corneal nerves.13
Tear osmolarity may increase as a result of decreased
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secretion of lacrimal gland protein, electrolyte and water
secretion, and in addition a drop in the blink rate, with an
increase in the evaporation of the tears.14 Increased tear
osmolarity induces ocular surface inflammation by activat-
ing stress kinases which alter the ocular surface.14 Another
mechanism associated with refractive surgery is LASIK-
induced neurotrophic epitheliopathy (LINE), in which cor-
neal staining is secondary to a reduction of blinking and
a decreased release of neurotrophic factors.14,15 Other
potential contributing factors include an inflammatory
response to surgery and frequent use of eyedrops with
preservatives, damage to the goblet cells by suction ring
induced pressure, altered tear-film stability caused by
changes in corneal curvature, medication-induced effects,
and even discontinued wear of eyeglasses.14,16,17 For some
patients, the sensations of dry eye could arise from spon-
taneous firing by the damaged or regenerating corneal
peripheral nerves causing pain of neuropathic origin, or
“phantom cornea”.18 Almost all patients will have transi-
ent dry eye in the postoperative period but the estimates of
prevalence vary widely with 40–59% at 1 month and
10–40% at 6 months.14,16,19,20 It is believed to resolve in
most cases within the first postoperative year, but other
studies have shown higher osmolarity 12 months after
LASIK and that nerve regeneration may not be complete
at 18 months.14,16,18,21 The majority of articles document-
ing dry eye after laser vision correction (LVC) surgery
include only a limited time of observation after surgery.
To the best of our knowledge, there are no studies evalu-
ating dry eye as long as 5 years or more after refractive
surgery.
The implantable collamer lens (ICL; STAAR Surgical,
Monrovia, CA), a posterior chamber phakic IOL (pIOL),
has a history of 30 years in refractive surgery around the
world.22 The procedure can be used to correct a higher
range of ametropia than LVC. Some patients may be better
candidates for ICL implantation due to pupil size, dry
eyes, inadequate tissue volume for LASIK, abnormal topo-
graphic shape or personal preferences for a reversible
procedure.23 While no studies specifically addressing dry
eye after ICL implantation are evident in the literature, it is
occasionally reported in general studies of the lens. In
a study of 56 patients having ICL, two patients reported
mild, and one reported moderate symptoms of dry eyes.23
Naj et al, in a meta-analysis of 7 studies (511 eyes)
comparing iris fixated pIOL and ICL, reported 1 incident
of clinical significant dry eye.24 Given the similarities of
the ICL procedure to cataract or Refractive Lens Exchange
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(RLE) surgery, some of the same risk factors for dry eye
should exist. Cataract surgery has been shown to indepen-
dently transiently induce or exacerbate dry eye; studies
have shown that dry eye symptoms increase after uncom-
plicated phacoemulsification but generally resolve after
about 3 months.8 The signs associated with post-cataract
dry eye include decrease in tear break up time, increased
ocular surface staining and changes in tear volume. The
presumed pathophysiological mechanisms underlying cat-
aract surgery induced dry eye include use of topical anes-
thetics, exposure desiccation, possible light toxicity from
the operating microscope, nerve transection, elevation of
inflammatory factors, goblet cell loss, and meibomian
gland dysfunction (MGD).8 The surgical trauma may
also affect corneal sensitivity, increase inflammation and
contribute to tear film instability.8
Since data were available for the ICL patients and limited
information exists in the literature on the frequency of DED
in this group, we chose to include these patients in our study.
ICL implantations are not associated with dry eyes or
reduced precision in IOL calculations so the ICL group
serves as an extra control group. The aim of this study was
to compare the prevalence of DED as determined by different
signs and symptoms in patients undergoing LVC or ICL 5 to
15 years ago to a similar population with no history of
refractive surgery, as unstable tear film may be
a confounding source of error in calculating IOL-power in
post-LVC patients. Long-term observation data can add to
our understanding of these sources of error in IOL calculation
for post-LVC patients in particular, to determine if it needs to
be given extra consideration in this population.
Patients and Methods
The study was a cross-sectional case-control study involving
data from the Ifocus private eye clinic in Haugesund,
Norway. Participants were recruited from patients who had
undergone LVC (LASIK or Femto-LASIK) or ICL 5–15
years ago. All surgeries were performed by the same surgeon.
LASIK surgeries were performed with Amadeus II micro-
keratome with superior hinge and 130-micron flap thickness.
Femto-LASIK (1 subject) were performed with Wavelight
FS 200 with superior hinge and 110-micron flap thickness.
ICL surgery was performed with a temporal 2,75 mm main
incision and two side ports at 60 degrees from the main
incision. The anterior chamber was filled with viscoelastic,
and the ICL (STAAR Surgical Company, Lake Forest, CA,
USA) was implanted into the anterior chamber. The haptics
were positioned behind the iris into the sulcus. Toric lenses
Clinical Ophthalmology 2020:14
Gjerdrum et al
were rotated to the planned axis. Surgical iridectomy was
performed near 12 o'clock position. Viscoelastic was
removed and pupil contracted using Miochol-E (Bausch
&Lomb Bridgewater, NJ 08807 USA)
Patients from a population who were pre-examined or
screened and found eligible for refractive surgery but who
had elected not to proceed were age matched and recruited
as controls. Eligible participants were identified from clin-
ical patient records, randomly selected and consecutively
recruited (by telephone, e-mail, or text message).
Recruitment and data collection were performed from
March 2018 to January 2019. The study followed the
tenets of the Declaration of Helsinki and was approved
by the Regional Committee for Medical and Health
Research Ethics in Norway (Ref no 2018/75). A written
informed consent was obtained.
Inclusion criteria were age over 20 years at the time
of original surgery, bilaterally good ocular health, with
no pathology or systemic disease involving the corneal
surface, and corrected visual acuity ≥0.1 logMAR at
the time of recruitment. Exclusion criteria were man-
ifest corneal scarring, lid deformities, any acute or
chronic disease or illness that would confound the
results of the study, pregnancy or lactation, recent
intra- or extra-ocular surgery, ICL patients who have
had a subsequent corneal refractive surgery (laser
touch-up), previous radial keratotomy, or other corneal
surgery besides LASIK (e.g. photorefractive keratect-
omy (PRK), Laser-assisted subepithelial keratectomy
(LASEK), transplant, lamellar keratoplasty). Patients
were instructed to not wear contact lenses on the
examination day and/or not to use any eyedrops for at
least 2 h before the examination.
One eye was randomly selected as the test eye.
Uncorrected distance visual acuity (UDVA), refraction
and corrected distance visual acuity (CDVA) were tested
after osmolarity and the other tests in the order
described below. A timespan of at least 5 mins was
given between the HD-analyzer and the Keratograph,
to allow for stabilization of the tear film. If some mea-
surements were not possible to obtain because of eye-
movements, blinking or other reasons, these patients
were rescheduled (if possible), and a complete new set
of measurements was taken. Otherwise, the test was
recorded as n/a. Visual acuity was recorded on
a Snellen chart and converted to logMAR. All testing
was done by one clinician (B.G.).
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Tear Film Osmolarity
Tear film osmolarity was measured with the Tearlab
Osmolarity System (Tearlab Corp., Escondido, California,
USA) Tear film osmolarity was selected as the primary
outcome measure for the study, as it is documented to have
an effect on repeatability of keratometry.3 Osmolarity was
always the first test on all patients, and both eyes were
measured as recommended by the manufacturer and because
commonly used criteria for DED involve the osmolarity in
both eyes. Testing was performed as described by the
manufacturer.25 It is suggested that a cut-off of 316 mOsm/
L is best for diagnosing moderate to severe DED.
Furthermore, a between-eye difference ≥8 mOsm/L is
a sign of loss of tear film homeostasis.7 As such, the cut-
off criteria for categorizing hyperosmolarity in this study
were the worse eye having an osmolarity of ≥316 mOsm/L
or a between-eye difference ≥8 mOsm/L.
Dynamic Ocular Scatter Index (OSI)
The optical quality of the tear film was assessed with the
HD Analyzer quality analysis system (OQAS) (HD analy-
zer, Visiometrics S.L., Terrassa, Spain). Details of the
system and testing procedure are described elsewhere.26
The dynamic Ocular Scatter Index (OSI) is recorded for
a total of 20 s. For each patient measurement, the device
calculates the mean OSI, the standard deviation (OSI St.d)
and the difference (OSI difference) between maximum
(OSI max) and minimum OSI (OSI min). The Vision
Break-Up Time (VBUT) is the time in seconds (maximum
10 s) before the subject’s OSI increases one unit from the
minimum observed value. The changes in OSI (OSI std,
OSI difference, and VBUT) are a result of tear film
dynamics as other opacities in the cornea, lens or vitreous
body do not change during the interblink interval.27,28 The
summary statistics for the OSI mean, OSI Standard
Deviation, OSI Difference and VBUT for all patients
were reported. The cut-off criteria for categorizing DED
were a VBUT< 10 s.
Subjective OSDI Questionnaire
The OSDI questionnaire is a validated and widely used
questionnaire for clinical trials related to the eye.7,29 Using
a total of 12 questions with a score from 0 to 4, the OSDI
score is obtained by multiplying the sum by 25 and divid-
ing by the number of questions answered. This yields
a score from 0 to 100, with higher scores representing
greater disability.29 For this study, only the total score
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was recorded. The cut-off criteria for categorizing DED
were an OSDI score ≥13.7
Non-Invasive Keratograph Break Up
Time (NIKBUT)
NIKBUT was assessed using the Oculus Keratograph 5M
(Oculus, Wetzlar, Germany). Placido rings are reflected on
the corneal surface. The system detects distortion in the
reflected mires which is recorded as a break in the tear
film. Details of the system and testing procedure are
described in the instruction manual and user guide.30,31
The system detects the 1st break-up time and average
break-up time (NIKBUT average) but only the latter was
reported in this study. Based on studies of fluorescein
break-up time (FBUT) and comparison between FBUT
and NIKBUT, our cut-off criteria for categorizing DED
were NIKBUT average ≤10 seconds.7,32–35
Meibography
Meibography was assessed using the meiboscan function
of the Oculus Keratograph 5M (Oculus, Wetzlar,
Germany). Meibography allows observation of the silhou-
ette of the meibomian gland morphological structure.7
Details of the system, testing procedure and grading are
described in the instruction manual and user guide.30,31
Results were recorded on a 0–3 (0.5 step) continuous
scale: Grade 0 (no loss of meibomian glands), Grade 1
(0-1/3 loss), Grade 2 (1/3−2/3 loss) and grade 3 (loss >2/
3). A study by Arita et al considered a summed meibo-
score of upper and lower eyelid ≥3 as abnormal.36 For this
study assessment of the lower eye lid was considered
sufficient.37 Based on this our criteria for categorizing
DED was a lower eyelid meiboscore of ≥1.5.
Schirmer 1
The Schirmer test was performed without anaesthesia
(Schirmer 1) using a Schirmer paper strip (HUB
Pharmaceuticals, Rancho Cucamonga, CA). It is
a standardized test, providing an estimation of stimulated reflex
tear flow.7 Details of the testing procedure are described
elsewhere.7 The cut-off criteria for categorizing DED was
≤10 mm after 5 mins, a threshold that is commonly accepted
in clinical trials.38
Analysis
Data were recorded on an Excel spreadsheet (Microsoft
Corp., Redmond, WA, USA). The data file from the HD
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Analyzer and the exported NIKBUT data from the
Keratograph were transferred to the data in the spread-
sheet, and cross checked. Descriptive statistics included
the minimum, maximum, mean, standard deviation and the
interquartile range (IQR). Statistical analysis was per-
formed using t-test, ANOVA or nonparametric tests as
appropriate and Pearson χ2 test was used for comparing
frequencies. Missing data were not included in the analy-
sis. A p-value0.05 (two-sided) was considered statistically
significant. Statistical analyses were performed using the
RStudio data-analysis software (version 1.2.1335) RStudio
Inc (Boston, MA, USA) and R Commander (version 2.60)
(R Core Team, Vienna, Austria).
Post Hoc Analysis
Correlations between osmolarity and other factors known
to affect dry eye (like age, sex, preoperative refraction,
time of day, and season), and between minimum OSI and
dynamic OSI were tested with Pearson´s correlation coef-
ficient of determination or Spearman’s rank correlation for
nonparametric variables.
Results
Subject demographics and refractive error are shown in
Table 1. A total of 893 patients were examined for elig-
ibility, 661 were found eligible, but 242 could not be
reached or lived too far away. Of the remaining 419
patients, 96(74%), 80(85%) and 85(67%) were recruited
in the LVC, ICL and control group, respectively. One
patient was excluded because of possible systemic disease,
two were excluded because of LVC surgery less than five
years ago, and one was excluded because of lactation.
A total of 257 patients were included in the study: 94
(45 females, 49 males) in the LVC group, 80 (57 females,
23 males) in the ICL group and 83 (41 females, 42 males)

Table 1 Demographics, Pre- and Postoperative Refraction and Visual Acuity

LVC, n=94 ICL, n=80 CTRL, n=83 p

Mean ± SD Mean ± SD Mean ± SD

(Range) (Range) (Range)

Sex: f % 47.9% 71.2% 49,4% 0.003 a*

Age, years 41.3 ± 6.3 40.8 ± 8.8 41.2 ± 8.1 0.905b

(29 to 57) (25 to 64) (23 to 56)

Years since treatment 7.7 ± 1.3 10.2 ± 3.1 <0.001c

(5.2 to 12.8) (5.0 to 14.7)

Pre-Tx MRSE, DS −2.76 ± 1.75 −6.10 ± 5.16 −1.38 ± 3.45 <0.001d*

(−8.00 to +2.37) (−17.12 to +8.00) (−9.37 to +6.87)

CYL, DC −0.94 ± 0.88 −1.40 ± 1.43 −0.87 ± 1.20 0.001e*

(−3.50 to 0) (−8.75 to 0) (−7.00–0)

BCVA, (logMAR) −0.05 ± 0.04 0.00 ± 0.07 −0.06 ± 0.07 <0.001e*

(−0.18 to 0.05) (−0.18 to 0.3) (−0.18 to 0.10)

Post-Tx MRSE −0.07 ± 0.38 −0.19+0.59 0.017f*

(−2.37 to +0.75) (−2.25 to +1.50)

CYL −0.19 ± 0.25 −0.38 ± 0.38 <0.001f*

(−1.0 to 0) (−1.50 to 0)

UCVA (logMAR) −0.03 ± 0.12 0.06 ± 0.16 <0.001f*

(−0.18 to 0.70) (−0.18 to 0.7)

BCVA (logMAR) −0.07 ± 0.05 −0.03 ± 0.06 <0.001f*

(−0.18 to 0.02) (−0.18 to 0.10)
Notes: aPearson´s χ2 test ICL difference from CTRL, bAnova (unequal variance), cWilcoxon rank-sum test between ICL/LVC, dKruskal–Wallis rank-sum test, eWilcoxon
rank-sum test difference between ICL and CTRL, fWilcoxon rank-sum test, *Statistically significant.
Abbreviations: LVC, Laser Vision Correction; ICL, Implantable Collamer Lens; CTRL, Control group; MRSE, mean spherical equivalent refraction; CYL, refractive cylinder;
BCVA, best-corrected visual acuity (logMAR); UCVA, uncorrected visual acuity (logMAR); Pre-Tx, historic data before surgery; Post-Tx, post-treatment data (study
examination).

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Gjerdrum et al
in the control group. The ICL group had significantly more
females vs the control group and significantly longer time
since surgery vs the LVC group. There were significant
differences in preoperative refraction between groups.
Table 2 summarizes the mean values of the various
testing results. None of the tests showed significant differ-
ences in mean values except for the OSI measures. The
OSI measures were significantly higher in the ICL group
compared to the control group. However, the minimum
OSI was significantly correlated to OSI Standard
Deviation, OSI Difference, and VBUT (Spearman´s Rho:
0.43, 0.45 and −0,33, respectively, p<0.01) for all subjects.
When results were categorized according to the cut-off
criteria described in the methods (Table 3), the frequency of
hyperosmolarity was significantly higher in the LVC group
vs the control group (73% vs 50%), but not significantly
different between the ICL and control group (Figure 1). The
frequency of VBUT≤10 s was significantly higher in the
ICL group vs the control group (33% vs 17%). No other
single objective tests or combination of criteria showed any
significant difference between LVC or ICL and the control
group. The frequency of OSDI ≥13 tended to be lower in the
LVC group relative to the control (19% vs 31%); this was
not statistically significant (p = 0.06). The frequency of
OSDI ≥13 in the ICL group was the same as the con-
trol (31%).
We could not establish any significant correlation
between osmolarity and any of the other single DED
tests. However, the frequency of hyperosmolarity was sig-
nificantly higher in patients with two or more other indi-
cators of DED (66% vs 52% mOsm/L, p=0.03).
There was no significant correlation between osmolarity
and pre-operative mean spherical equivalent refraction
(pre-MRSE) for the LVC group alone. Stepwise multivari-
ate analysis including all patients tended towards a positive
correlation between osmolarity and age and pre-MRSE
(Pearson´s R2 =0.08, p < 0.01 and 0.03, respectively).
While significant, these correlations are weak. An example
of this is shown in Figure 2; it can be seen that several
outliers are influencing the fit. The single eye osmolarity
cut-off value of 316 mOsm/L is shown for reference.
Discussion
The main objective was to compare the prevalence of DED
as determined by different signs and symptoms in patients
with previous refractive surgery to a control group, because
this may affect keratometry measurement and therefore IOL
calculation at the time of cataract surgery. Epitropoulos et al
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compared repeatability of keratometry in a hyperosmolar
and a normal group. In the hyperosmolar group, 8% had
a difference of more than 0.50 D, and 5% had a difference of
more than 1 D while all subjects had less than 0.5 D in the
normal group.3 For a patient with previous myopic LVC,
a difference in keratometry of 1D could give approximately
0.8 D to 1.2 D difference in refractive outcome when using
post-LVC IOL calculation formulas.39 The contribution of
errors from tear-film instability could be relatively small
when compared to sources of error like keratometric index
error and incorrect estimate of the effective lens position.
However, these errors are attempted solved in the post-LVC
IOL formulas. While average prediction error for several
Post-LVC formulas are within ± 0.5, it could range from
+1D to −2D.40,41 Arguably, in the cases with highest pre-
diction errors, several factors probably contribute, like dia-
meter error, actual IOL position, and erroneous
keratometric measurement due to unstable tear film may
be another. Therefore, it is interesting to know if previous
LVC patients have higher risk of unstable tear film than
patients without prior refractive surgery.
Although not shown in mean osmolarity of the test
eye, when using cut-off values as described, we found
that the prevalence hyperosmolarity was significantly
higher in the LVC group vs the control group and the
ICL group. This is likely a consequence of the fact that
both intra- and inter-eye variability of osmolarity is
a hallmark of DED.42 The prevalence of DED in both
the LVC group and the control group was relatively high
compared to some other studies. One study reported
osmolarity greater than 308mOsm/L in 30% at 12
months after LASIK.21
De Paiva et al found that dry eye was associated with
preoperative myopia and ablation depth at 6 months after
surgery, possibly because of nerves needing to regenerate
a longer distance in the case of deeper ablation depth.20 We
did not find correlation between pre-MRSE and Osmolarity
in the LVC group. This difference may be explained in that
our subjects had 5 years or more since surgery and differ-
ences in regeneration due to ablation depth have been leveled
out. A meta-analysis by Feng et al found significantly higher
tear-BUT, less loss of sensation and less corneal staining in
patients with horizontal hinge flap compared to superior
hinge flaps, but all our patient had nasal hinge except for
one Femto-LASIK patient.16
A meta-analysis in the DEWS II epidemiology report
found prevalence of DED in the general population varying
from 14% to 39% based on symptoms, and 16% to 86% based
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Table 2 Mean Values and Standard Deviation of Different DED Tests (Test Eye)
LVC ICL CTRL p

Clinical Ophthalmology 2020:14

Mean ± SD n Mean ± SD n Mean ± SD n
(Range, IQR) (Range, IQR) (Range, IQR)

Osmolarity test eye (mOsm/L) 311 ± 17 92 305.9 ± 11 80 309.7 ± 14 82 0.183a

(281 to 383, 16) (282 to 330, 12) (290 to 370, 14)

OSI Minimum 1.1 ± 0.6 93 1.6 ± 1.1 79 1.2 ± 0.6 81 <0.001b*

(0.2 to 3.8, 0.7) (0.4 to 7.6,1.1) (0.3 to 3.2, 0.7)
OSI St.d 0.4 ± 0.4 0.4 ± 0.5 0.2 ± 0.3 0.002b*
(0.0 to 1.8, 0.4) (0.0 to 2.2, 0.5) (0.0 to 2.0, 0.2)
OSI Difference 1.4 ± 1.3 1.8 ± 1.8 1.1 ± 1.1 0.003b*
(0.1 to 5.5, 1.5) (0.2 to 9.0, 2.0) (0.1 to 6.9, 1.0)
VBUT 9.1 ± 2.5 8.4 ± 3.2 9.1 ± 2.2 0.054a
(0.5 to 10.0, 0) (0.5 to 10.0, 1.75) (1.0 to 10.0, 0)

OSDI 10 ± 13 94 11 ± 12 80 10.9 ± 10.5 83 0.438

(0 to 67, 8) (0 to 65, 15) (0 to 50, 14)

NIKBUT avg. (seconds) 17.1 ± 5.6 91 16.8 ± 5.6 77 16.8 ± 6.0 80 0.921
(4.9 to 25.0, 9.0) (4.5 to 25, 9.2) (4.7 to 25.0, 9.8)

Meibography 0.5 ± 0.7 94 0.3 ± 0.5 78 0.4 ± 0.7 80 0.300

(Meiboscore) (0.0 to 3.0, 0.7) (0.0 to 2.2, 0.4) (0.0 to 3.0, 0.5)

Schirmer 1 13 ± 9 94 14 ± 11 76 15 ± 11 82 0.968
(mm) 0 to 35, 12 0 to 35, 15.0 (0 to 35, 20)
Notes: aKruskal–Wallis rank-sum test. bWilcoxon rank-sum between ICL and CTR, *Statistically significant.
Abbreviations: SD, standard deviation; IQR, Interquartile range; LVC, Laser Vision Correction; ICL, Implantable Collamer Lens; CTRL, Control group; OSDI, Ocular Surface Disease Index; NIKBUT, non-invasive keratograph break-up
time; OSI, Ocular scatter index; OSI mean, mean OSI for each patient; OSI St.d =standard deviation of OSI for each patient; VBUT (Vision break-up time), the time before an increase in OSI of 1 unit due to tear break-up.

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Table 3 Prevalence of DED as Determined by Signs and Symptoms

Treatment group LVC ICL CTRL

Test variable (Cut-off values) % n pa % n pa % n

Osmolarity 73.3% 90 0.002* 46.2% 80 0.63 50% 82

(≥316 either eye or ≥8 inter-eye diff.)
VBUT (≤10 seconds) 24.7% 93 0.23 32,9% 79 0.02* 17,3% 81
OSDI (≥13) 19.1% 94 0.06 31.2% 80 .99 31.3% 83
NIKBUT avg 12.1% 91 0.32 15.6% 77 0.75 17.5% 80
(≤10 seconds)
Meibography 10.6% 94 0.68 5.1% 78 0.37 8.8% 80
(meiboscore ≥1.5)
Schirmer 51.1% 94 0.76 48.7% 76 0.99 48.8% 82
(mm wetting ≤10mm)
OSDI and one other indicator 18.1% 94 0.55 27,5% 80 0.39 21.7% 83
Notes: Pearson's χ : difference from control. *Statistically significant.
a 2

Abbreviations: LVC, Laser Vision Correction; ICL, Implantable Collamer Lens; CTRL, Control group; OSDI, Ocular Surface Disease Index; NIKBUT avg, average non-
invasive keratograph break-up time; VBUT, HD analyzer Vision break up time.

on signs.43 Gupta et al found abnormal osmolarity
(>307mOsm/L in either eye or an inter-eye difference
>7mOsm/L) in 57% of 120 patients (including 25 patients
with previous refractive surgery) presenting for cataract
surgery.44
The relative high prevalence of DED in all groups
could possibly be related to the fact that many patients
who have problems with contact lenses due to dry eyes
consider refractive surgery as a solution, and up to 73% of
LVC patients have been reported to seek surgery because
of difficulties with contact lens wear.14,45 There are several
risk factors for developing dry eye after LASIK, with pre-
existing dry eye being the most significant.14,46 Konomi
et al suggested that lower preoperative tear volume may
increase the risk of chronic dry eye.47 In addition, age is
a risk factor for DED and the LVC and ICL groups in this
study were on average 8 and 10 years older, respectively,
than at time of their surgery.6

Prevalence of DED as determined by signs and symptoms

80% p=0.002*
73%

70%

60%

50% 51%
50%
49% 49% Control
46%
ICL
40% p=0.02* LVC
33%
31% 31%
30%
25%
p=0.06*
19%
20% 17% 18%
16%
12%
11%
10%
9%
5%

0%
Osmolarity (≥316 either Visual BUT OSDI (≥13) AVG BUT Meibography Schirmer 1
eye or ≥8 inter-eye diff.) (≤10 seconds) (≤10 seconds) (meiboscore ≥1.5) (wetting ≤10mm)

Figure 1 Comparing the prevalence of DED as determined by different tests between LVC or ICL and control group.
Notes: *Pearson's χ2: difference from control group.
Abbreviations: BUT, Break-up time; OSDI, ocular surface disease index; AVG, average; ICL, Implantable collamer lens; LVC, laser vision correction.

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Figure 2 Example of weak correlations, here between osmolarity and age. Several outliers are influencing the fit. The single eye osmolarity cut-off value of 316 mOsm/L is
shown for reference.
The mean of the dynamic OSI measures was signifi-
cantly higher in the ICL group, but these measures were
correlated to the minimum OSI (before tear film changes).
The introduction of a pIOL into an optical system could
reduce the optical quality of the system significantly,48 so
the increased OSI values in the ICL group may be a result
of reduced optical quality. The device software normalizes
measurement to compensate for different levels of scatter,
but this might not be sufficient in the case of a pIOL.
There was a tendency for fewer subjective symptoms in
the LVC group. Studies have shown that subjective and
objective symptoms may not agree due to differences in
age, tolerance, environment and even long-standing dry eye
which can reduce sensitivity.3,43 In post-LASIK patients, it
may be that reduced symptoms are due to reduced sensitivity.
A review report by Shtein found that studies of nerve mor-
phology have shown reduced density 3–5 year after
surgery.49 This strengthens the hypothesis that LASIK sur-
gery can induce and even mask dry eye permanently due to
incomplete nerve regeneration. In consequence, the recom-
mendation in the DEWS II report on diagnosing DED by
subjective symptoms and one homeostasis marker may not
be optimal for post-LVC patients.7
We could not establish a significant correlation between
osmolarity and other single dry eye tests. The lack of correla-
tion between different diagnostic tests is likely
a consequence of the multi-factorial nature of DED and the
fact that different diagnostic tests reveal different aspects of
Clinical Ophthalmology 2020:14
Gjerdrum et al
the disease.50,51 However, we did find that patients with two
or more other indicators of DED showed a significant higher
frequency of hyperosmolarity. Classification of dry eyes is
usually based on several tests, but tear osmolarity has been
shown to be the best single metric both to diagnose and
classify DED and evidence indicates that tear hyperosmolar-
ity contributes to, and is representative of, the mechanisms
involved in the development and progression of DED.42,51 In
a review report by Potvin et al they found that a majority of
the studies reviewed supported the use of tear osmolarity as
a tool of diagnosis and severity grading.50
There are some limitations to the study. There was
a risk of selection bias as patients were informed about
the study on recruitment and patients with symptoms may
have been more interested in participating, but the propor-
tion of patients who agreed to participate was high and the
subjective symptom score was low. Factors such as sys-
temic or topical drugs and occupation should be the same
across groups, but where not controlled and might have
influenced our findings. There were significantly more
females in the ICL group, though there was no correlation
between sex and osmolarity. Also, there were significant
differences in pre-MRSE, but only weak correlation
between pre-MRSE and osmolarity. The study included
patients with a large span of years since surgery and
there were significant differences in this time span
between groups, but there was no correlation between
years since surgery and osmolarity. In addition, the first
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Gjerdrum et al
surgeries were as long as 15 years ago and surgical tech-
niques may have changed, which might have influenced
our findings relative to those that are more recent. Our
study included only LASIK and Femto-LASIK surgeries,
so we did not address whether LASEK or PRK affects
dry eye.
Conclusion
Osmolarity differences suggested a significantly higher
prevalence of DED in patients who underwent LVC 5 to
15 years ago than in a matched control group, though the
LVC group had fewer subjective symptoms. The recom-
mendation in the DEWS II report on diagnosing DED by
subjective symptoms and one homeostasis marker may not
be optimal for post-LVC patients. Hyperosmolarity
increases the risk for tear film instability which is likely
to be a confounding source of error for post-LVC IOL
calculations. Further studies of post-LVC tear film quality
are advocated. For instance, of interest is the potential
effect of reduced tear quality on repeatability of measure-
ments with different types of keratometers.
Disclosure
Bjørn Gjerdrum reports grants from The Research Council of
Norway, grants from SkatteFUNN R&D tax incentive scheme,
grants from Memira AS, during the conduct of the study. The
authors report no other conflicts of interest in this work.
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